Among young women (<40), breast cancer incidence is higher among black women than white women, but at older ages, incidence is higher among white women than black women. The 'black-white crossover' in incidence has been interpreted as evidence of intrinsic biological differences in young, black women's breast cancer. In support of intrinsic biological differences in black vs. white tumors, our work in the Carolina Breast Cancer Study (CBCS), a large population-based case-control study that oversamples young African American (AA) women, demonstrated that young black women are more likely to get basal-like breast cancer (a poor prognosis cancer) and less likely to develop luminal breast cancer (the cancer with the best prognosis). However, we hypothesize that beyond intrinsic subtype (and within basal-like and luminal subtypes), there are additional biological differences in black vs. white tumors that arise due to ancestral differences in expression of genes involved in breast cancer progression. To understand the contribution of ancestry and race-related markers to cancer progression, it is important to (1) study expression and gene sequence differences in both tumor tissue and normal tissue, and (2) to identify the mechanistic implications of these expression differences in breast cancer and normal cells. Aim 1 of this project will perform expression and gene sequence studies of tumor tissues to identify race-related changes that are also associated with cancer progression, while in Aim 2 the expression and gene sequence of normal tissue will be used to evaluate whether these progression-related genes differ prior to disease onset. These first two aims will use both tumor and normal tissues from two well characterized populations (Carolina Breast Cancer Study and the Normal Breast Study) with substantial proportions of African American patients. These biospecimens will be used to perform RNA-sequencing for quantitative gene expression, and gene sequence analysis, to identify race-associated gene expression differences and polymorphisms that contribute to cancer progression and mortality disparities. Having identified key expression and sequence differences, in Aim 3 will study these genes and their pathways in breast cell lines to evaluate their effects on normal morphogenesis and on cancer progression. The data from this project will identify new biological targets in race-associated breast cancer mortality and will identify the mechanisms by which race-associated gene expression differences promote tumor progression among African American women.